京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18894号 / 医博第4005号 / 新制||医||1009(附属図書館) / 31845 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 泰広, 教授 戸井 雅和, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg 2017. / Neck pain is one of the most common debilitating musculoskeletal complaints seen in physiotherapy practice. It is often associated with headache, upper back and shoulder/arm pain (cervico-brachial pain) and such patients are more disabled than patients with neck pain only. Cervico-brachial pain syndrome is an upper quarter pain syndrome in which neural tissue sensitivity to mechanical stimulus is thought to play a role. Neuropathic pain is a problem associated with and prevalent in neck and arm pain. Psychosocial factors, such as fear-avoidance beliefs and catastrophising, have been shown to play an important role in treatment outcomes. Neural mobilisation (NM) is often used to influence the neural structures in conditions with signs of neural involvement or neural mechano-sensitivity. It seems reasonable to use neural mobilisation in cervico-brachial pain as neural structures play an important role in this condition The optimal treatment intervention for cervico-brachial pain is yet to be established. The prevalence of cervico-brachial pain in a South African population is also unknown. Aims of the study The aims of the study were to: i. To establish the prevalence of cervico-brachial pain in patients being seen in physiotherapy practices in Pretoria, South Africa. ii. To establish the effect of neural mobilisation on the pain, function and quality of life of patients with acute and sub-acute cervico-brachial pain. iii. To establish the influence of high catastrophising scores and neuropathic pain on treatment outcomes. iv. To establish the effect of demographic factors on the pain, function and quality of life of patients with cervico-brachial pain. Methods Research Question 1. A retrospective survey of physiotherapy patient records dated 1 January 2011 to 31 December 2011 was conducted. The prevalence of patients with neck pain in relation to other musculoskeletal complaints was calculated and expressed as a percentage. Symptoms recorded included the following; headache, dizziness, pins and needles, feeling of weakness, other sensations, more than one symptom and pain in other area/s. Based on body charts, areas of pain were coded as neck pain only, pain in the shoulder, shoulder and upper arm, shoulder to elbow, lower arm, hand, neck and arm up to wrist, neck and arm including hand. Research Questions 2, 3 and 4 A single blind randomised clinical trial was conducted to establish the effect of neural mobilisation on cervico-brachial pain. The intervention group (IG) received cervical and thoracic mobilisation exercises, advice and NM. The usual care (UC) had the same treatment without NM. Outcomes were assessed at 3 weeks, 6 weeks, 6 months and 12 months. The Numerical Pain Rating Scale was used to determine the effect of NM on pain. The Patient Specific Functional Scale was used to determine the effect of NM on function and the EuroQual5 instrument was used to establish the effect of NM on the quality of life. At 6 weeks the Global Rating of Change was administered to measure patient’s perception of recovery. The Neuropathic Diagnostic Questionnaire (DN4) was used to classify patients with neuropathic pain and the Pain Catastrophising Scale to identify catastrophisers. Results and Discussion Prevalence of neck and radiating arm pain in physiotherapy private practice, Pretoria South Africa The prevalence of neck pain in private physiotherapy practices in Pretoria, SA is high (46.4% of the total musculoskeletal complaints) with radiating arm pain (52.2% of neck pain population) and pain in other areas (22.6% of neck pain population) being commonly associated with neck pain. Furthermore, other symptoms such as headache (25.4% of the neck pain population) and paraesthesia (11.2%) are also frequently present. Neck pain is multi-faceted and this has implications for its management. Future studies with a bigger, representative population sample are needed to establish the prevalence of neck pain in SA. The effect of neural mobilisation on cervico-brachial pain All patients improved significantly in terms of pain, function and quality of life over the 12-month period. However, the IG had significantly less pain than the UC group at 6 months (p=0.03 95% CI 0.96 - 2.03) and this difference was more pronounced in patients with neuropathic pain (IG 2.91 95%CI 1.74 - 4.08 and CG 5.5 95% CI 3.45 - 7.55 p=0.01). There were no significant differences between groups in terms of function or quality of life. Patients with neuropathic pain had significantly more pain at 6 months (positive neuropathic pain 3.71 95%CI 2.57 – 4.84; negative neuropathic pain 1.44 95% CI 0.93 – 1.96 p=0.0001) and 12 months (positive neuropathic pain 3.23 95% CI 1.74 – 4.71; negative neuropathic pain 1.38 95% CI 0.88 – 1.91 p=0.01) compared to those without neuropathic pain. At 12 months function was also negatively affected by the presence of neuropathic pain (positive neuropathic pain 23.91 95%CI 20.96 – 26.86; negative neuropathic pain 27.15 95% CI 25.95 – 28.36 p=0.04). It did not have an effect on quality of life. Catastrophisers had more pain at 6 months (catastrophisers 4.25 95% CI -1.90 – 10.40; non-catastrophisers 1.70 95% CI 1.22 – 2.17 p=0.02) and 12 months (catastrophisers 3.56 95% CI 1.10 – 6.02) compared to non-catastrophisers (1.47 95% CI 0.96 – 1.99 p=0.02). There was no difference in their function at any time, however at baseline they reported a lower quality of life (Catastrophisers 61.96 95% CI 52.04 – 71.87; non-catastrophisers 75.79 95% CI 71.91 – 79.66 p=0.002). Conclusion The addition of NM to cervical and thoracic mobilisation, exercises and advice to stay active, in the management of cervico-brachial pain, resulted in less pain at 6-month follow-up. For patients with neuropathic pain the positive effect was more pronounced. Adding NM as an adjunct to usual care is effective to improve pain for patients with cervico-brachial pain especially for those with a neuropathic pain component. The presence of neuropathic pain and catastrophising resulted in poor pain-related outcomes. / MT2017

OBJECTIVE: The incidence of endocervical adenocarcinoma has increased steadily over the past two decades. Since the Bethesda System was introduced, the diagnosis of atypical glandular cells of undetermined significance (AGUS) has also risen and now accounts for 0.461.83% of all cervical (Pap) smears. The purpose of this study was to evaluate the significance of a diagnosis of A GUS using cytohistologic correlation. STUDY DESIGN: A retrospective review of archival material from 1993 through 1996 identified 64 patients who had smears diagnosed as AGUS and had a subsequent surgical biopsy. The smears were reviewed and cytologic features analyzed and correlated with the histologic diagnosis. RESULTS: On biopsy, 3 (5%) of the 64 cases showed endocervical adenocarcinoma in situ (AIS) (1 case with invasive adenocarcinoma also), 14 (22%) had a benign glandular lesion (endocervical polyp, tubal metaplasia, microglandular hyperplasia, reactive changes), 35 (54%) had squamous intraepithelial lesion (SIL) (15 diagnosed on the original smear), and 12 (19%) had no abnormality. Among the cytologic criteria evaluated, feathering (P = .01), palisading (P < .001) and chromatin clearing (P = .002) were shown to have a significant association with the histopathologic diagnosis of AIS/adenocarcinoma. These features were also useful in distinguishing AIS/adenocarcinoma from SIL and benign glandular changes from AIS/adenocarcinoma but not benign/reactive glandular changes from SIL. CONCLUSION: A diagnosis of AGUS correlated with a clinically significant lesion in the majority of cases. Squamous dysplasia (SIL) was the most common lesion identified. The presence of feathering, nuclear palisading and chromatin clearing increased the likelihood of a histologic diagnosis of AIS/adenocarcinoma.

In the normal ectocervix, mitoses are rare and are usually confined to the basal layers. In contrast, they occur more frequently in cervical intraepithelial neoplasia (CIN) and are seen at higher levels, suggesting that CIN may be associated with a progressive dysfunction in proliferative activity of cervical cells. The objective of this study was to use proliferating cell nuclear antigen (PCNA) immunohistochemistry to examine the proliferative activity of cervical epithelial cells in CIN lesions. Sixty- eight cervical biopsies were examined; 20 were totally benign, 14 had CIN I, 21 CIN II, and 13 CIN III. In benign epithelia, PCNA staining was usually confined to the basal layers, whereas in CIN the staining was seen at progressively higher levels of the epithelium. There was a statistically significant correlation between the CIN grade and the highest level of PCNA staining (PCNA grade, r = 0.746, P < 0.001). In addition, the PCNA grade showed significant correlation with the highest level at which mitoses were seen (mitosis grade, r = 0.706, P < 0.001), and a strong direct correlation between the mitosis and CIN grades was also observed (r = 0.955, P < 0.001). These data demonstrate that (1) PCNA immunoreactivity in neoplastic cervical epithelium is different from that seen in the normal cervix, suggesting that CIN is associated with a dysfunctional proliferation of cervical epithelium, (2) that there is a significant correlation between the PCNA grade and CIN grades, and (3) the 'mitosis grades' have a strong correlation with the CIN grades.

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Cervical cancer is the second most common cancer affecting women in developing countries and accounted for 84% of the global incidence of cervical cancer in 2012. Nicaragua is one country illustrating this disparity, with an annual cervical cancer mortality six times the U.S. rate. This may be explained by lack and poor utilization of effective screening programs, especially the Papanicolaou, or Pap, smear. This study resulted from a partnership formed by faculty and students from two U.S. universities and a Nicaraguan nonprofit organization to conduct projects to benefit a community in Nicaragua. To promote a free Pap smear program provided by the local clinic, a community-wide survey regarding Pap smear utilization was conducted with local health promotoras (promoters). Of 1,117 women, 78.4% reported ever having a Pap smear, of whom 11.1% had not received their results, while results were reported as normal by 78.9%, and abnormal by 10%. The most common reasons for not having a Pap smear were refusal to test, fear, and pain. Proportions of women who ever had a Pap smear varied by etapa (stage/neighborhood, p < .001). Findings are useful for policy development to improve the clinic’s screening services and encourage full utilization of Pap smears.

Cervical cancer is the fourth most common cancer in women. It is caused by the hu- man papillomavirus (HPV). There are many different types of HPV, some of which are high-risk, highly associated with cancer, and low-risk. While HPV is very common— most sexually active individuals will contract some sexually transmitted HPV infec- tion in their lifetime—most infections are cleared without any complication. However, persistent infections may establish and develop into cancerous lesions. Two vaccines have been developed against the two most high-risk types, and have shown high lev- els of efficacy thus far. However, infections are still occurring and it is not clear why some individuals develop persistent infections while others do not. In this thesis, we develop a model to describe how the infection spreads within the host. We express the basic reproduction number R0, a threshold for the establishment of an infection. We solve for the diseased equilibrium, providing insight about whether an infection will persist or not. We develop a spatial model to examine how spatiality of the infec- tion process affects the establishment or clearance. Lastly, we develop a multi-type HPV model to examine whether competitive HPV types are able to coexist in the host for different levels of competition. Ultimately, this work provides groundwork for within-host modelling of HPV and can provide direction for future research. / Thesis / Master of Science (MSc) / The human papillomavirus (HPV) is a sexually transmitted infection that is known to cause cervical cancer in women along with other genital cancers. Cervical cancer is the fourth most common cancer in women, and thus researchers are looking to reduce the number of cervical cancer cases and the number of HPV infections. In order for HPV to cause cervical cancer, the infection must persist for a long time. Most individuals clear the infection without any complication; however, some individuals develop persistent infections. By using mathematical and computation models, we hope to understand why and how HPV infections spread in the host. We develop a criterion for when the infection may be able to establish in the host, and explore conditions that could lead to clearance. Understanding when and how infections will persist could inform treatment and monitoring of cervical cancer development.

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